Integrated Concentration Of Growth Hormone Research Articles

DECREASED GROWTH HORMONE (GH) BINDING TO IM-9 CELLS IN CHILDREN WITH BIOLOGICALLY INACTIVE GH SYNDROME (BI)

We measured the ratio of radioreceptor assayable (RRA) to radioimunoassayable (RIA) GH in: a/ Fifteen normal stature children and young adults (controls), b/ Seven poorly growing children (neurosecretory; NS) who had normal GH RIA responses to stimulation but deficient 24-hour integrated concentration of GH (IC-GH). c/ Six poorly growing children (bioinactive; BI) who had normal GH secretion both to stimulation and IC-GH. The BI group was 9.1±3 (mean ± SD) years of age, bone age 6.1±2.7 years, IC-GH 6±2.4 ng/ml (normal 3.2-12). On GH therapy the growth rate of BI patients increased from 3.2±0.5 cm/yr to 8.8±1.9 cm/year.RRA was a modification of a previously reported RRA using IM-9 lymphocytes. The RRA/RIA was 1.3±0.4 in controls, 1.5±0.7 in NS and 0.6±0.6 in BI patients. The difference in RRA/RIA between BI patients and controls was significant (P<0.005).We conclude that 1/ The circulating GH of NS patients has a normal binding affinity to IM-9 cells. 2/ Decreased binding to IM-9 cells may be a clinically useful diagnostic test for BI.

Growth Hormone (GH) Response to GH-Releasing Hormone in Children with Subnormal Integrated Concentrations of GH*

We determined the GH responses to human GH-releasing hormone-40 (GHRH) in poorly growing children who had either normal or deficient GH secretion, as measured by pharmacological stimulation and integrated concentration of GH (IC-GH). Ten patients had both normal pharmacologically stimulated GH and IC-GH (GH-normal), 15 patients had normal pharmacologically stimulated GH but deficient IC-GH [GH neurosecretory dysfunction (GHND)], and the remaining 7 patients had both subnormal stimulated GH and IC-GH [GH deficiency (GHD)]. The mean peak plasma GH response to GHRH was 11.7 +/- 8.5 (+/- SD) ng/ml in GHD patients, significantly lower than the responses of both the GHND (49.2 +/- 39.2 ng/ml; P less than 0.0001) and GH-normal (51.8 +/- 44 ng/ml; P less than 0.0001) groups. The range of peak GH responses to GHRH in GHD patients overlapped the lower end of the range of responses in the GHND and GH-normal patients. Three GH-normal and eight GHND patients had greatly enhanced GH responses to GHRH (greater than 50 ng/ml); no GHD patients had a response over 24.2 ng/ml. There was no difference between the GH responses of male and female patients within groups to GHRH. There was a significant correlation between the log of the peak GH response to GHRH and the log of the maximal GH response to standard pharmacological stimuli (r = 0.51; P less than 0.005). Because of the variability of GH responses to GHRH encountered among the patients, the response to GHRH cannot be used as a test for identifying patients with inadequate spontaneous GH secretion. The IC-GH is the only method that can identify children with GHND.

Suppression of the Growth Hormone (GH) Response to Clonidine and GH-Releasing Hormone by Exogenous GH*

GH release in response to clonidine and human GH-releasing hormone-(1-44) (hGHRH-44) was assessed in 11 boys (aged 7-14 yr) with short stature, who had normal GH secretion. The response to these 2 provocative stimuli was repeated after, respectively, 2 and 3 days of treatment with human GH (0.1 U/kg, im). Exogenous GH significantly blunted the response to both clonidine [the mean 2-h integrated serum GH concentration falling from 1050 +/- 350 (+/- SEM) to 749 +/- 297 ng/ml X min; P = 0.03] and hGHRH-44, the 2-h integrated GH concentration falling from 1553 +/- 358 to 547 +/- 202 ng/ml X min; (P = 0.03). Plasma insulin-like growth factor (IGF-II) concentrations did not change after GH administration. In contrast, plasma IGF-I (somatomedin-C) concentrations increased from 97 +/- 16 ng/ml before administration of GH to 142 +/- 32 ng/ml (P = 0.05) after two days and 149 +/- 23 ng/ml (P less than 0.01) after the third treatment day. However, no correlation was found between the changes in response to clonidine or hGHRH-44 and changes in circulating levels of IGF-I. Our data confirm the existence of GH-dependent feedback inhibition of GH release during childhood and suggest that this inhibition operates, at least in part, at the level of the pituitary. While participation of the IGFs/somatomedins in this feedback loop cannot be excluded, the inhibitory effects of exogenous GH do not depend directly on circulating plasma IGF-I or IGF-II levels.

The effects of cranial irradiation on growth hormone secretion.

Growth hormone (GH) secretion has been studied under physiological conditions and in response to standard pharmacological stimuli in 14 children, who had previously received cranial irradiation between two and fourteen years earlier. All fourteen showed a blunted GH response to insulin hypoglycaemia and, in twelve, the GH response to arginine stimulation was also subnormal. Physiological GH secretion was studied by measuring integrated GH concentrations in 30 min blood samples collected over a 24 hour period by a continuous withdrawal pump. Compared to normal controls (n = 5), the irradiated patients showed a significant reduction in the mean integrated GH concentration (2.2: 8.8 mU/l; p less than 0.002), the total 24 hour GH output (mean 105.7 mU vs. 391.7 mU; p less than 0.002) and the mean GH output during the first six hours of sleep (mean 48.2 mU vs. 226 mU; p less than 0.002). There was no significant correlation between the maximum peak GH response to either pharmacological test and the total 24 hour GH output. Conventionally most short children undergo two provocative tests of GH release and if the GH response to one of the two tests is normal, it is usually assumed that GH production is adequate. Adopting these criteria in this study it would have been assumed incorrectly that GH production was normal in two children. Nonetheless all 14 children showed a blunted GH response to an ITT as well as a reduced total 24 hour GH output.(ABSTRACT TRUNCATED AT 250 WORDS)

21 THE EFFECTS OF CRANIAL IRRADIATION ON GROWTH HORMONE SECRETION

Children with radiation-induced damage to the hypothalamicpituitary axis have been described in whom the GH response to a pharmacological test is normal but 24 hour GH production is diminished. Therefore we have studied GH secretion under physiological conditions and in response to standard pharmacological stimuli in 14 children (9-17 years), who had received cranial irradiation between two and 14 years earlier. All 14 showed a blunted GH response to an ITT (1-14 mU/l) and, in 12, the GH response to arginine stimulation was also subnormal (1.4-19 mU/l). Physiological GH secretion was studied by measuring integrated GH concentrations in 30 minute blood samples collected over a 24 hour period by a continuous withdrawal pump. Compared to normal controls (n=5), the irradiated patients showed a significant reduction in the mean integrated GH concentration (2.2 : 8.8 mU/l; p < 0.002), median total 24 hour GH output (89.6 : 340.7; p < 0.002) and the median GH output during the first six hours of sleep (32.7 : 210; p < 0.002). There was no significant correlation between the maximum peak GH response to either pharmacological test and the total 24 hour GH output. All 14 children showed a blunted GH response to an ITT as well as a reduced total 24 hour GH output. Therefore we would suggest that in children suspected of radiation-induced GH deficiency pharmacological tests of GH secretion remain useful, the ITT being the test of choice because of the marked radiation sensitivity of the hypoglycaemic stimulus.

506 SHORT CHILDREN SECRETE INSUFFICIENT QUANTITIES OF GROWTH HORMONE

We compared the 24-h integrated concentration of growth hormone (IC-GH) from 46 children of normal stature (NS) with 90 short children. Nineteen of the short children had classical GH deficiency (GHD) by standard pharmacologic growth hormone stimulation tests. Seventy-one children had normal GH (NGH) responses to stimulation. The mean IC-GH of NS (6.6±1.9 ng/ml) > NGH (3.8±2.3 ng/ml) > GHD (1.6±0.6 ng/ml), differences between groups were all statistically significant (P<0.0001). Forty-five percent of NGH children had IC-GHs within the range of the GHD group and this may be the explanation for their poor growth. Thus, NGH is a mixed group of patients with a spectrum of spontaneous GH secretion ranging from normal to impaired. Fourteen NGH children with low IC-GH (<3 ng/ml) were treated with GH. Ten of them had an increase in growth rate of 50% or more from pretreatment growth rate.Conclusion: l/The IC-GH test is indicated for all children who present with clinical feature of GH deficiency even if their GH response to pharmacological stimuli is normal. 2/GH therapy of NGH children with low IC-GH levels can promote significant improvement in growth rate.

464 TESTOSTERONE (T) BUT NOT OXANDROLONE (OX) INCREASES SPONTANEOUS GROWTH HORMONE (GH) AND SOMATOMEDIN-C (SmC) CONCENTRATIONS IN BOYS WITH CONSTITUTIONAL DELAY OF GROWTH AND ADOLESCENCE (CDGA)

The effect of T and OX on GH and SmC concentrations was studied in boys with CDGA. Ten boys received OX (0.1 mg/kg/d) for 65±5 d and 5 boys received T propionate (7.5 mg IM × 7 d) followed by T enanthate (100 mg IM q mo for 3 mo). Serum GH was measured in samples obtained q 20 min for 24 hr before and 65±5 d into therapy. SmC levels were measured twice during the same 24 hr period before and 65±5 d into therapy. The 24 hr integrated concentration of GH (ICGH) was obtained from the mean of 72 samples and compared to that obtained from a pooled sample (p=NS). A pulse of GH was recorded if the peak level rose >5 ng/ml. We found no differences in the ICGH, in the number of GH secretory episodes, or in the SmC levels in boys treated with OX. However, in boys treated with T there were significant increases in the ICGH, the number of GH secretory episodes and in the SmC levels.We conclude that testerone therapy doubles the amount of GH secreted daily, although OX at 0.1 mg/kg/d is without effect. This increase in GH secretion may contribute to the increased growth rate at puberty.

434 ENHANCED RESPONSE TO hpGRH-40 IN GROWTH HORMONE NEUROSECRETORY DYSFUNCTION

In growth hormone neurosecretory dysfunction (GHND), poor growth is due to low 24-h integrated concentration of GH (IC-GH) even though the response to paired pharmacologic stimulation (PS) of GH is normal. We compared the GH response to 1 μg/kg hpGRH-40 of 8 GHND children, 4 children with subnormal GH responses to paired PS tests and subnormal IC-GH (GHD), and 3 short children with normal PS and normal IC-GH (NORMAL SHORT). The peak GH response to hpGRH-40, PS stimulation and IC-GH of the 3 groups is presented as mean±lSD in ng/ml: The response to hpGRH-40 of GHND children was significantly higher than the other groups. Conclusion: 1/GHND children have an increased reserve of releasable GH. 2/GHND lack the neurologic GRH releasing mechanism to maintain adequate spontaneous GH release. 3/The increased response of GHND to hpGRH-40 may be of diagnostic value.

The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals.

We examined changes in spontaneously secreted growth hormone with aging by studying the 24-h integrated concentration of GH (IC-GH) of 173 nonobese subjects (height, greater than or equal to 5%; 7-65 yr of age). There was no significant difference in IC-GH on repeat testing of 13 men or in 23 women studied in the follicular and again in the luteal phase of the menstrual cycle. The level of IC-GH was strongly effected by age; children had the highest mean IC-GH, and there was a decline in IC-GH with increasing age after the second decade of life. The correlation of IC-GH with age was highly significant (r = 0.73; P less than 0.0001). There was no difference in IC-GH between males and females when matched for age. The mean IC-GH at Tanner stage 5 of puberty (7.4 +/- 2.0 ng/ml) was higher than that at stages 2-4 (5.7 +/- 1.4; P less than 0.0005) or that in prepubertal children (5.8 +/- 1.4; P less than 0.001). Thus, age and pubertal status must be carefully considered when interpreting the IC-GH for patients suspected of having deficient or excessive secretion of GH.

Clinical application of serum insulin-like growth factor I (IGF-I)(26-46) radioimmunoassay--with special reference to the relationship between IGF(26-46) and growth hormone secretion

Serum insulin-like growth factor I(IGF-I)(26-46) levels were determined in normal children aged 0-16y(n = 111), adults(n = 11), and various diseased conditions. In order to elucidate a mutual relationship between IGF-I(26-46) and growth hormone (GH) secretion, the following correlations were evaluated: 1) a correlation between IGF-I(26-46) and basal GH level (n = 57), 2) a correlation between IGF-I(26-46) and GH level responding to the insulin tolerance test (ITT) (n = 30), 3) a correlation between IGF-I(26-46) and an integrated concentration of GH(ICGH) in the early sleep stage (n = 24). In addition, the following correlations between GH level with ITT and ICGH in the early sleep stage(n = 20) and between IGF-I(26-46) and an integrated concentration of prolactin (ICPRL) in the early sleep (n = 20) and overnight sleep (n = 7) stages were also examined. IGF-I(26-46) was measured according to the method of Yanaihara with minor modifications. Samples for ICGH were collected every 30 min until 4 hours after sleep by a portable continuous flow blood withdrawal pump(CORMED, MODEL ML6) at a rate of 6 ml/h. Samples for ICPRL from 13 subjects were collected by the same procedure and period as ICGH. On the other hand, samples for ICPRL from 7 subjects were collected during an overnight period. Sleep and wake cycles were almost identical in the subjects tested. Among the subjects tested with ITT and continuous blood sampling for ICGH and ICPRL, patients with pituitary dwarfism were excluded. Serum IGF-I(26-46) levels appeared to be age-dependent, and the highest value was demonstrated in puberty. Some children under 8 years of age showed serum IGF-I(26-46) levels as low as that of pituitary dwarfism. No sexual difference was noticed in IGF-I(26-46) levels. Serum IGF-I(26-46) levels in pituitary dwarfism were apparently low and significantly increased after hGH injection. Serum IGF-I(26-46) levels in patients under 11 years of age with constitutional dwarfism and Turner's syndrome revealed an almost normal result. However, many patients over 11 years of age showed lower levels of serum IGF-I(26-46) than normal subjects, and some cases showed remarkably low levels of serum IGF-I(26-46). Serum IGF-I(26-46) levels in precocious puberty without treatment were slightly high in comparison with age-matched controls.(ABSTRACT TRUNCATED AT 400 WORDS)

RESPONSE TO THERAPY IN CHILDREN WITH LOW INTEGRATED CONCENTRATION OF GROWTH HORMONE

We have previously demonstrated that the response of GH to pharmacologic stimulation does not always correspond to the actual integrated concentration of GH (ICGH)(JCEM 48:811, 1979). Spiliotis et al have reported that 3 of 7 children who had a normal response to GH provocative tests but a reduced amplitude or frequency of GH pulses, responded to GH therapy (Abstract 528 Endocr. Soc. 1983).

Integrated concentrations of growth hormone, insulin, C-peptide and prolactin in human obesity

Twenty-four hour integrated concentrations of growth hormone (IC-GH) were significantly lower in young, obese subjects than in young subjects who were lean. Significant inverse correlations were found between IC-GH and body mass index (BMI) as well as the IC-GH and the 24 hr integrated concentrations of insulin (IC-I) and C-peptide (IC-C) in obese subjects below 30 yr of age. Since IC-GH decreases with age, the effect of obesity on IC-GH could not be demonstrated in the older subjects; a weak inverse correlation ( p < 0.05) between IC-GH and IC-C was found. Prolactin was significantly lower in the older subjects but did not correlate with IC-GH and was similar in lean and obese. Lipid deposition in adipose cells is promoted by high concentrations of insulin as well as low concentrations of growth hormone. We found a significant correlation between the IC-I IC-GH ratio and BMI of both the young and older subjects. Correlations between these two factors do not necessarily imply a cause and effect relationship. It is plausible, however, that the elevated IC-I IC-GH of the obese may facilitate their lipid storage and counter their efforts at weight reduction.

Regulation by catecholamines of spontaneous growth hormone secretion in the baboon

To gain an increased understanding of the role of central neurotransmitters in the regulation of spontaneous growth hormone (GH) secretion in the primate, we investigated the effects of peripheral intravenous infusion of the alpha-adrenergic receptor-blocking agent, phentolamine (5.0-mg bolus and 1.5 mg . kg-1 . 12 h-1), and the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine (MPT, 300 mg . kg-1 . 24 h-1), on the pattern of GH secretion in five adolescent male baboons. Serum GH concentrations were measured in blood samples taken at 20-min intervals over 12 h (0530-1730) after an overnight fast. In nontreatment control studies, GH secretion exhibited a predictable rhythmic oscillation with a mean period of 5.7 +/- 0.4 (SE) h. Phentolamine significantly decreased the 12-h mean and integrated GH concentrations compared to control values, but the small peaks of GH, which could be distinguished from base-line concentrations in three of the animals, occurred at the same time as during control studies. Whereas alpha-methyl-p-tyrosine slightly reduced serum levels of GH, it significantly increased the GH pulse frequency in the baboons. A two- to fourfold increase in serum prolactin levels occurred in all animals treated with MPT. These findings suggest that alpha-adrenergic pathways play a stimulatory role in maintaining spontaneous daytime GH secretion in the baboon and that one or more catecholamines are involved in the generation of rhythmic GH release.

Comparison of Physiological and Pharmacological Tests of Growth Hormone Function in Children with Short Stature*

We studied 30 short-statured children to investigate their 24-h integrated serum concentration of GH (ICGH) and its diurnal pattern and to compare this data with their responses to standard stimulation tests for GH release. Eight patients with normal stimulation tests had a mean (+/- SD) ICGH value of 8.0 +/- 3.8 ng/ml (range, 4.5--16.4), and all had several secretory peaks greater than 12 ng/ml. Nineteen patients with abnormal responses (peak, less than 10 ng/ml) had a mean ICGH value of 2.7 +/- 1.9 ng/ml (range, less than 0.8 to 7.0); this was significantly lower than that of control subjects and patients with normal stimulation tests. However, 5 of these patients had normal ICGH values. Three patients with borderline stimulation test responses (10--12 ng/ml) had normal ICGH values (3.2, 3.4, and 11.9 ng/ml). Of the 22 patients with either abnormal or borderline stimulation tests, 14 had an ICGH result below the range of normal. Of these 14, 11 had no secretory peaks greater than 10 ng/ml, whereas 3 had peaks between 10--12 ng/ml. The 8 other patients had ICGH results in the normal range. Despite significant correlation (r = 0.668), integrated GH values did not correlate with stimulation tests in a minority of the patients, the status of whom remains to be determined by long term response to exogenous GH therapy.

302 PROVOCATIVE AND INTEGRATED CONCENTRATIONS OF GROWTH HORMONE (GH) IN DIVERSE GROWTH DISORDERS

Since provocative tests for GH release may not reflect normal GH secretory patterns, we studied 18 children with diverse growth disorders, age 7-18 yrs, by two standard stimuli (L-Dopa, arginine,insulin-induced hypoglycemia) and by continuous blood withdrawal (collected hourly) for 12 and 24 hr integrated GH concentrations (ICGH). Tests were started at 0800 hr; 12 hr ICGH was calculated for 1800-0600 hrs. Six patients with normal stimulation tests (peak > 10 ng/ml) had 12 hr ICGH = 5.2 ± 2.6 ng/ml (mean ± S.D.; range 2.5-9.1); two boys with delayed adolescence had no hourly peak > 10 ng/ml. Five patients with borderline stimulation tests (peak GH 7-10 ng/ml) had 12 hr ICGH 4.0 ± 2.3 (range 1.5-6.7); in 3/5, the peak integrated hourly levels were low: 4.5, 4.7, 8.7. Seven patients with low stimulation tests (peak < 7 ng/ml) had 12 hr ICGH 0.75 ± 0.6 ng/ml (range 0.18-1.96); all had hourly peak ICGH < 3.5 ng/ml and 6/7 had clinical evidence of GH deficiency. Patients with delayed puberty had borderline or normal provocative GH; however, 4/5 had low 12 hr ICGH and hourly peaks. There were highly significant correlations between ICGH peak, 12 hr ICGH and peak provocative GH (p < 0.001). In all groups, 12 hr ICGH correlated with 24 hr ICGH (p < 0.001). With the exception of one child with obesity, growth velocities correlated more closely with ICGH than with provocative GH. Constant withdrawal may be helpful particularly in patients with borderline provocative tests and/or sexual immaturity.

Measurement of the 24 hour integrated plasma concentration of growth hormone, in assessing the response of acromegalic patients to treatment.

The integrated concentration of growth hormone (ICGH) has been measured in fourteen acromegalic patients, and compared with the basal plasma growth hormone concentration (BGH). Seven patients were treated by trans-sphenoidal pituitary surgery, and in these, similar percentage reductions of BGH and ICGH occurred after treatment. The other seven patients were treated with bromocriptine alone, and in these the percentage reduction of ICGH was significantly less than that of BGH. Measurements of basal plasma growth hormone concentration may be unreliable in assessing the response of acromegalic patients to treatment with bromocriptine. The ICGH can be measured easily on a single blood specimen obtained by continuous sampling over 24 h, and may be more reliable for this purpose.

Circadian variation of integrated concentration of growth hormone in children and adults.

A portable constant withdrawal pump was used to determine consecutive 30-min integrated concentrations of growth hormone (ICGH) for a 24-h period in 18 normal subjects, ages 5 to 28 yr. Seven prepubertal, 5 pubertal and 6 young adult subjects were studied under conditions of normal activity. Pubertal, prepubertal, and adult subjects had peaks during waking hours as well as during sleep, but peaks in the adults were usually lower than in the children. Using an analysis of variance, a significant (P smaller than 0.01) downward trend of ICGH was observed to occur during sleep. During waking hours a significant variation (P smaller than 0.01 by analysis of variance) was found with low levels in the first few hours after awakening and an upward trend as the evening approached. Food intake had no significant effect on ICGH nor did the introduction of the indwelling catheter. The mean apparent half-life values of growth hormone calculated on the basis of 87 episodes with 3 or more points on the downslope was 40.1 min. This is significantly higher than the known true half-life of the hormone, suggesting that complete secretory inactivity after a secretory episode is an infrequent event.

Growth Hormone: Metabolic Clearance Rates, Integrated Concentrations, and Production Rates in Normal Adults and the Effect of Prednisone

A constant withdrawal pump was used to determine the integrated concentration of growth hormone (ICGH) which was used in conjunction with the metabolic clearance rate (MCR) of growth hormone (GH) to calculate the GH production rates (GHPR) in normal adults, acromegalics, and normal controls receiving prednisone. The mean ICGH for 22 premenopausal females on no medication was 3.0+/-1.6 ng/ml (sd) which is significantly lower (P < 0.005) than the mean of 6.6+/-2.9 for 10 women receiving oral contraceptives and significantly higher than the means of 1.5+/-0.75 for 5 postmenopausal females (P < 0.05) and 1.8+/-1.0 for 16 adult males (P < 0.01) which are comparable. The mean GHPR's in mg/24 hr per m(2) for the four groups are: normal females = 0.52+/-0.24 (sd), females receiving contraceptive pills = 1.65+/-0.58 (P < 0.005), postmenopausal females = 0.26+/-0.12 (P < 0.025), and adult males 0.35+/-0.23 (P < 0.025).Three untreated acromegalic patients had ICGH's of 59, 82, and 93 ng/ml and GHPR's ranging from 14.5 to 17.9 mg/24 hr. Prednisone in a dose of 20 mg t.i.d. for 8 days significantly decreased both the ICGH and GHPR. Alternate day prednisone (60 mg in a single q.o.d. dose) resulted in less consistent inhibition of GH release which may play a role in the more normal growth seen in children receiving q.o.d. prednisone.

Integrated concentrations of growth hormone correlated with plasma testosterone and bone age in preadolescent and adolescent males.

ABSTRACT The integrated concentration of growth hormone (ICGH) was studied in 17 normal preadolescent and adolescent boys and 16 normal adult males. The ICGH was determined over a 16–24 hour period under normal ambulatory conditions without the use of exogenous stimuli. The mean ± SD ICGH of 5.6 ± 3.6 ng/ml for the boys is significantly higher than the mean of 1.8 ± 1.0 for adult males. There is not an increase in ICGH associated with increase in bone age, progression of puberty, or increase in plasma testosterone. ICGH is markedly elevated in some boys prior to onset of puberty or elevation of plasma testosterone. This is in contrast to earlier reports that both exogenous and endogenous androgens may stimulate the growth hormone response to arginine and/or insulininduced hypoglycemia.